Effects of Bepridil and Pimozide, Existing Medicines Capable of Blocking T-Type Ca2+ Channels, on Visceral Pain in Mice.

Abstract

T-Type Ca2+ channels (T-channels), particularly Cav3.2, are now considered as therapeutic targets for treatment of intractable pain including visceral pain. Among existing medicines, bepridil, a multi-channel blocker, used for treatment of arrhythmia and angina, and pimozide, a dopamine D2 receptor antagonist, known as a typical antipsychotic, have potent T-channel blocking activity. We thus tested whether bepridil and pimozide could suppress visceral pain in mice. Colonic and bladder pain were induced by intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) and systemic administration of cyclophosphamide (CPA), respectively. Referred hyperalgesia was assessed by von Frey test, and colonic hypersensitivity to distension by a volume load with intracolonic water injection and spontaneous bladder pain were evaluated by observing nociceptive behaviors in conscious mice. The mice exhibited referred hyperalgesia and colonic hypersensitivity to distension on day 6 after TNBS treatment. Systemic administration of bepridil at 10-20 mg/kg or pimozide at 0.1-0.5 mg/kg strongly reduced the referred hyperalgesia on the TNBS-induced referred hyperalgesia and colonic hypersensitivity to distension. CPA treatment caused bladder pain-like nociceptive behavior and referred hyperalgesia, which were reversed by bepridil at 10-20 mg/kg or pimozide at 0.5-1 mg/kg. Our data thus suggest that bepridil and pimozide, existing medicines capable of blocking T-channels, are useful for treatment of colonic and bladder pain, and serve as seeds for the development of new medicines for visceral pain treatment.

• Authors: Maho Tsubota, Kazuki Matsui, Saaya Fukushi, Kyoko Okazaki, Fumiko Sekiguchi, Atsufumi Kawabata
• Journal: Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 44 Issue 3 Pg. 461-464 ( 2021) ISSN: 1347-5215 [Electronic] Japan
• PMID: 33642557 (Publication Type: Journal Article)

Chemical References

• Analgesics
• Calcium Channel Blockers
• Calcium Channels, T-Type
• Dopamine D2 Receptor Antagonists
• Pimozide
• Bepridil
• Cyclophosphamide
• Trinitrobenzenesulfonic Acid

Topics

• Analgesics (therapeutic use)
• Animals
• Bepridil (therapeutic use)
• Calcium Channel Blockers (therapeutic use)
• Calcium Channels, T-Type
• Colitis (chemically induced, drug therapy)
• Cyclophosphamide
• Cystitis (chemically induced, drug therapy)
• Dopamine D2 Receptor Antagonists (therapeutic use)
• Female
• Male
• Mice
• Pimozide (therapeutic use)
• Trinitrobenzenesulfonic Acid
• Visceral Pain (chemically induced, drug therapy)